Cardiac Involvement in Monkeypox Outbreak

Unusual presentations and uncommon clinical manifestations of Monkeypox (Mpox) in the current outbreak highlight the need to focus on cardiac symptoms of the virus. Owing to limited discussion regarding cardiac involvement in recent cases of Mpox, we conducted a scoping review to determine the range of existing research and provide a descriptive overview of the current literature on these manifestations. This review was conducted using a previously developed six-stage methodological approach and keeping in view the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR). Records retrieved from PubMed, ScienceDirect and Google Scholar, using a two-step search strategy, were subjected to title and abstract screening, followed by full text screening of remaining articles against specified eligibility criteria. Relevant information was extracted and summarized. Our search yielded 707 records. Following title and abstract screening, 23 articles were retrieved for full text screening. Finally, a total of nine articles were included in this review (three case series and six case reports discussing a total of 13 patients). Myocarditis was identified as the most frequently reported cardiac manifestation of Mpox. Novel clinical presentations included pharyngitis, sore throat, proctalgia, and perianal irritation. Most patients reported chest pain as the primary symptom of cardiac system involvement. Elevated troponin was the most commonly reported investigation finding followed by an elevated C- Reactive Protein. There exists a lack of high-quality studies investigating cardiac system involvement in the current outbreak of Mpox. More information is needed regarding risk factors for cardiac complications, disease progression, and cardio tropism and immunological response to improve preventive/therapeutic strategies. We highlight the paucity of relevant data and call for further discussion to improve the understanding of cardiac manifestations of Mpox. This scoping review sheds light on the underexplored cardiac manifestations of Mpox and highlights the need for heightened awareness of cardiac symptoms in the current outbreak.

patients reported chest pain as the primary symptom of cardiac system involvement.Elevated troponin was the most commonly reported investigation finding followed by an elevated C-Reactive Protein.There exists a lack of high-quality studies investigating cardiac system involvement in the current outbreak of Mpox.More information is needed regarding risk factors for cardiac complications, disease progression, and cardio tropism and immunological response to improve preventive/therapeutic strategies.We highlight the paucity of relevant data and call for further discussion to improve the understanding of cardiac manifestations of Mpox.This scoping review sheds light on the underexplored cardiac manifestations of Mpox and highlights the need for heightened awareness of cardiac symptoms in the current outbreak.

Introduction
As the world had begun to recover from the damage coronavirus disease 2019 (COVID-19) had caused, health systems around the globe were faced with another emerging infection the cases of which, although date back to the 1950s, became a public health emergency of global concern only recently.
As of January 31, 2023, over eighty-five thousand people in 110 countries have been reported to be infected with Monkeypox (Mpox) 1 .Only seven of these countries, in the region of Central and West Africa, have had reports of Mpox in the past 2 .Over the past couple of months, as the spread of the disease intensified and became more widespread, more than ten thousand new cases have been documented and four new geographical locations have been impacted 2 .With the emergence of cases in non-endemic regions, the World Health Organization (WHO) declared it a global health emergency in July 2022, having issued an alert two months earlier in May 2 .Since then, reports of cases in new locations have uncovered clusters of novel clinical manifestations that provide important insight into the clinicopathological differences of the current cases from the previous ones.
Patients with Mpox infection typically report nonspecific prodromal symptoms such as fever, fatigue, malaise, and headache, however, in the current outbreak, presentation with classic lesions without a prodromal phase is not uncommon 2 .The cutaneous lesion classically presents as singular vesicles or a cluster of painful umblicated papules having centrifugal pattern of distribution with local lymphadenopathy and a myriad of systemic symptoms 2 .However, skin lesions with unusual distribution and characteristics have been documented over the genitalia, anus, and perianal area.Additionally, anorectal manifestations such as proctitis, tenesmus, diarrhea, and proctalgia have also been reported 2 .Similarly, pharyngitis, tonsillar lesions, and epiglottitis are some of the oropharyngeal presentations of the novel Mpox outbreak 2 .Other uncommon presentations include ocular lesions such as conjunctivitis 3 , as well as certain cardiovascular manifestations.As cardiac symptoms of Mpox remain underdiscussed, we performed a scoping review to assess the extent, range, and nature of available research and to provide a descriptive summary of the existing literature on these manifestations using a systematic approach.
This review was undertaken using the six-stage methodological approach developed by Arksey and O'Malley 4 , presented in their 2005 guidelines titled 'Scoping studies: Towards a methodological framework', which is also in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR).With reports of unusual presentations and uncommon clinical manifestations of Mpox, a broad review question, in line with the recommendations for scoping reviews, was developed to guide the course of this review: What are the manifestations of cardiac involvement in patients diagnosed with Mpox in the current outbreak?This scoping review only included previously published scientific literature, without direct involvement of any patient population, therefore, ethical committee approval was not required.

Identifying Relevant Studies
In order to identify articles reporting cardiac manifestations in Mpox patients, a thorough literature search was performed on the following databases: PubMed, ScienceDirect, and Google Scholar using a two-step search strategy.First, an initial search of the information sources listed above was undertaken using key terms, modified accordingly for each database, separately and in combination.The search string employed to retrieve relevant data on PubMed is provided in In the next step, citation lists of relevant studies were manually screened to develop a comprehensive list of literature eligible to proceed to the screening process.

Study Selection Process
Eligibility criteria: Primary literature, published in the English language from January 2022 to January 2023, that reported cardiac manifestations in patients of Mpox, was considered eligible for inclusion without any restrictions regarding race, geographical location, gender, or setting.Letters, correspondence, opinions, perspectives, and book chapters were excluded.Studies evaluating cardiac complications of monkeypox vaccines were also not included.Before each phase, a pilot stage was conducted to ensure understanding of eligibility criteria between reviewers and the level of agreement was measured using the Cohen's Kappa with a value of >0.8 required to initiate the complete screening process.
Study screening process: Following the removal of duplicates, screening of extracted articles was carried out using a two-step process.During the first phase of screening, title/abstract of extracted studies were screened independently and in duplicate by two authors using Rayyan.In case of any disagreement during title/abstract screening, the article was included.Title/abstract screening was followed by full-text screening of the remaining articles.Any disagreement during the second phase of screening was resolved through mutual discussion and consensus.The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flowchart developed to systematically present the article screening process has been shown in Figure 1.

Data Charting
A structured data extraction form was developed on Microsoft Excel and checked independently by two reviewers for clarity and relevance.Key data points from each article were extracted which included the Author name, article type, and country of affiliation of corresponding author.Data pertaining to the objectives of this scoping review included; age of the patient, sex of the patient, presenting complaint, characteristics of cutaneous lesions, sexual history, comorbidities, previous and concurrent sexually transmitted diseases (STDs), investigation findings, diagnosis, management, duration of hospital stay, and patient outcome.

Collating, Summarizing, and Reporting the results
The final version of the summary of findings extracted was revised to include feedback from all co-authors and results obtained are discussed in detail under the relevant heading.

Search Results and Characteristics of Included studies
Using the two-step search strategy, our search yielded a total of 707 records from the three databases.Following the removal of duplicates, a total of 683 articles were considered eligible for screening.Of these, 662 articles failing to meet the eligibility criteria were excluded, and 23 articles were retrieved for full-text screening.Finally, a total of nine articles were included in this review, which included three case series [5][6][7] , and six case reports [8][9][10][11][12][13] , discussing a total of 13 patients.Out of these articles, two each were published from Canada and the United States of America, while one article each was published from institutions based in France, Portugal, Italy, Spain, and Pakistan.Summary of all 13 cases has been presented in Table 2 and Table 3.

Patient Characteristics
Age of the patient was reported in 10/13 cases with a median age of 33 years ranging from 21 to 51 years.All of the patients included in this review were men.Out of the 13 patients, three were reported to be positive for the Human Immunodeficiency Virus (HIV) 7,10,13 , while three had been previously treated for Syphilis 6,7 , and one had previous history of Human Papillomavirus Condyloma 11 .Pre-exposure prophylaxis for HIV was reported in two patients 6,9 .
Moreover, asthma and obstructive sleep apnea (OSA) were reported comorbidities in one patient 7 , and one case had been previously treated for OSA, external hemorrhoids, and obesity 7 .

History of Sexual Contact
A total of 53.84% (7/13) patients had a history of sexual contact with a same sex partner [5][6][7]10,11,13 . Two patints reported a history of sexual contact with a partner of opposite sex 5,8 .One patient reported having sexual contact with multiple partners 6 .Sexual history in the remaining patients was unclear.

Table 4. Summary of novel presentations and cutaneous lesions described in 13 patients included in our review
A total of four patients reported novel clinical presentations documented in the current Mpox outbreak.These included pharyngitis 11 , sore throat 7 , proctalgia 5,7 , and perianal irritation 7 .Some patients were also concurrently diagnosed with STDs along with Mpox, which included chlamydia and Herpes simplex virus-2 (HSV-2) 7 .

Cardiac Manifestations
Most of the patients reported chest pain as the primary manifestation of cardiac system involvement [5][6][7][8]12,13 . Otherpresentations included chest tightness 9 , dyspnoea 6 , palpitations 5 , and epigastric pain radiating to chest 11 .The characteristics of chest pain have been documented in Table 3 and percentage of occurrence of each symptom involving the cardiac system is given in

Diagnosis
A definitive diagnosis was provided for 10 of the 13 patients, with Mpox-associated acute myocarditis being the most common cardiac manifestation which was observed in 70% of these patients 5,6,8,9 .Other diagnosis included pericarditis 12 , and acute myopericarditis 11,13 .Two patients were labelled having 'demand ischemia' 7 , and another patient was only noted to have an increased CPK 10 -no definitive diagnosis was reached for these three patients.

Management
Most of the patients received supportive care for acute myocarditis 6,9,13 as summarized in Table 6.One patient diagnosed with Mpox associated pericarditis received therapy with 1gm Aspirin 8hourly for 14 days 12 .Tecovirimat was the most commonly employed antiviral medication used in this patient population 5,6,8,11 .Certain other medications used were ceftriaxone for chlamydia 8 , doxycycline for syphilis of unknown latency 6 , valaciclovir for HSV-2 7 , dexketoprofen 11 , colchicine 11 , bisoprolol 5 , and ramipril/angiotensin converting enzyme-inhibitors 5,8 .Almost all of the patients recovered without complication.

Discussion
Given the atypical clinical manifestations, diverse modes of transmission and rapid spread from endemic to non-endemic areas, Mpox is emerging as a significant global health concern 14 .Thus, it is important not to undervalue the onset of chest pain in an infected patient, which should trigger immediate cardiac investigations.

Cardiovascular events following vaccination
There appears to be a considerable overlap in the antigenic properties of various Orthopoxviruses such as variola virus, cowpox virus, and the Mpox.
Several reports have documented that patients with hemorrhagic smallpox can develop acute onset latestage myocarditis 15 .These findings have also been replicated in Crab-Eating Macaque model using the cowpox virus which mimics hemorrhagic smallpox in humans 15 .Furthermore, smallpox vaccine is strongly linked to post-vaccination myocarditis, with a reported incidence of 12 per 100,000 vaccinations 16 .The incidence of myocarditis following administration of ACAM2000 is 3.6 times greater among the vaccinated USA military personnel 17,18 .Within this group, definite vaccinia myocarditis was reported in 1 out of every 10,000 vaccinated individuals, typically manifesting 8 to 14 days after receiving the smallpox vaccine.In addition to these, less frequently reported adverse events involving the cardiac system include dilated cardiomyopathy and cardiac ischemia 17,18 .The vaccine against smallpox called the 'JYNNEOS' is prepared using the Vaccinia virus as the inoculating agent and has a reported efficacy of 85% against Mpox 8 .As a result of these viruses' similar antigenic or immunogenic properties, it can be extrapolated that Mpox may also cause myopericarditis via direct cardiac tropism or by an immune-mediated response.

Cardiac Manifestations of Mpox
As indicated by the results of our scoping review, myocarditis was the most prevalent cardiac lesion among the 13 patients included in our review with acute chest pain as the most frequently reported symptom of cardiac system involvement.In addition to myocarditis and pericarditis, recently published literature reports congestive heart failure 17 , arrythmias 19 , and vascular complications 20 following Mpox infection.

Pathogenesis of Mpox-induce Myocarditis
The mechanism by which Mpox may cause inflammation of the myocardium remains largely unclear given the limited data available regarding Mpox associated myocarditis.The primary pathogenic process of viral myocarditis involves lymphocytic infiltration coupled with myonecrosis, which usually becomes evident at around 10 to 14 days following infection 21 .Previously published literature reports direct damage caused by viral antigens as one of the possible mechanisms of myocardial injury.The virus may directly invade the myocardium and undergo replication within the cardiac myocytes, resulting in inflammatory disease 22,23 .However, an absence of evidence of direct viral infection of myocardial cells observed on histopathological investigation suggests that the mechanism of myocarditis in Mpox and other orthopoxvirus infections may be immunemediated 6,24 .Furthermore, the most frequently reported histologic finding associated with viral myocarditis is infiltration of the myocardium with lymphocytes.Additionally, edema of myocardial interstitium has also been reported.This is further suggestive of the immune-mediated pathophysiology of Mpox induced myocarditis 23 .An inflammatory response, characterized by the infiltration of immune cells, release of proinflammatory cytokines, and activation of cytotoxic T cells, results from the binding of viral genome to the immune cells that triggers the immune system 22 .This complex interplay between direct damage induced by the virus and the immune response is likely to contribute to the development of myocardial inflammation and subsequent impairment of cardiac function 25 .This inflammation of the myocardium may be selflimiting or progress to severe fulminant myocarditis 26 .Further research is warranted to achieve a thorough understanding of the pathological mechanisms underlying myocarditis development in individuals with Mpox.

Pathogenesis of Mpox-induced Pericarditis
Pericarditis refers to the inflammation of the pericardium surrounding the heart.As indicated by our findings, as well as previously published literature, Mpox can cause pericarditis through direct invasion and immune mediated mechanisms 22 .The pericardium may be directly invaded by the virus or an immune response following viral invasion may be observed 27 .
The differential diagnoses of inflammatory cardiac complications in presence of mucocutaneous lesions and lymphadenopathy are vast, hence the diagnosis of these complications in Mpox cases becomes challenging.Thus, it is imperative to maintain a broad perspective when encountering such presentations.Considering the recent surge in cases and diagnostic uncertainty associated, a criterion is overdue to escalate the clinical suspicion of cardiac complications in patients with suspected or diagnosed Mpox.

Investigations and Management
The following clinical characteristics should prompt further investigations to identify Mpox as the underlying cause: 1) Diagnostic criteria satisfying clinically suspected myocarditis/pericarditis; 2) ECG showing ST changes, T-wave, or PR-segment abnormalities; 3) Temporally related to constitutional symptoms of a viral infection such as fever, myalgia, fatigue, headache, and/or other flulike symptoms; 4) Painless or painful umblicated, vesiculopapular, and/or vesiculopustular lesions on skin with local lymphadenopathy; 5) Other novel manifestations of Mpox such as ocular, oropharyngeal, and/or anorectal; 6) History of sexual contact with a male or female partner within the last 3-17 days; 7) Common differentials ruled out via serology or Polymerase Chain Reaction (PCR).Investigations such as complete blood count, CRP, and cardiac troponins along with electrocardiogram and echocardiography play a crucial role in reaching the diagnosis of myopericarditis.Though Endomyocardial biopsy (EMB) is the gold standard for the diagnosis of myocarditis, it is not commonly performed given the invasive nature of the procedure 9 .
Therefore, cardiac MRI remains the non-invasive gold standard for the prompt diagnosis of myocarditis 9 .
Although the treatment strategy adopted will depend mainly on the severity of the presenting symptoms as well as the presence of any complications, the management of Mpox-induced cardiac lesions remains largely supportive 28 .For mild cases of viral myocarditis, supportive measures include taking rest, maintaining fluids and reducing inflammation 6 .In considerably severe cases, hospital admission with strict monitoring, and advanced interventions may become mandatory.Antiinflammatory agents and immunosuppressive drugs may be employed 29 .For pericarditis, the use of NSAIDs, colchicine, corticosteroids in addition to supportive measures have been recommended 30 .Our results show that almost all patients made full recovery with no reported complications, but myopericarditis may have a significant impact on the prognosis as well as the quality of life of the patients, thus highlighting the need for accurate diagnosis 31 .Despite the positive outcome of myocarditis in some patients, caution is advised as the limited number of reported cases calls for further research.Thus, individuals with Mpox should promptly seek medical attention if they have chest pain.In countries with Mpox outbreaks, healthcare providers should consider Mpox as a potential cause if at-risk patients are diagnosed with myocarditis 5 .

Limitations
Although our review provides a broad overview, it does not present the depth of the existing literature and thus makes the conduct of a meta-analysis Additionally, quality assessment of the case reports meeting eligibility criteria was not performed since it falls beyond the scope of a scoping review.A descriptive summary of the results has been presented without any statistical aggregation of extracted data which is beyond the objectives of this scoping review.Overall, this scoping review provides a broad overview of the topic and calls attention towards the limitations of the existing literature.

Future Recommendations
Our scoping review has revealed a significant dearth of high-quality studies investigating the cardiac system involvement in the current outbreak of Mpox.The studies that were eligible for inclusion in our review were primarily limited to case reports and case series, highlighting the need for more rigorous research in this area.The current literature lacks information on potential risk factors that may predispose certain patient populations to cardiac complications associated with Mpox, as well as factors that may predict progression to severe disease.Additionally, there is a need to gain a deeper understanding of the underlying pathology of the cardio tropism of Mpox and the immunologic response generated by the virus in order to develop effective preventive and therapeutic strategies.The indications for antiviral therapy in patients with Mpox and cardiac involvement, as well as the choice of antiviral for these patients, remain unresolved questions.

Conclusion
Through this scoping review, we draw attention to the paucity of relevant data and advocate for increased research efforts to better understand the cardiac manifestations of Mpox.Larger, welldesigned studies are necessary to establish a link between monkeypox and myocarditis and determine the course of disease and development of complications.It is worth noting that Mpox, like many viruses, exhibits a diverse range of manifestations, and prompt action is necessary to effectively manage and prevent inflammatory cardiac complications associated with Mpox.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flowchart showing the article screening process

Table 5 .
Percentage of occurrence of cardiac symptoms in 13 patients discussed in our review

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It is crucial to recognize novel cardiac manifestations in case of the current Monkeypox outbreak, to guide comprehensive surveillance, preparedness, and response efforts.
28. Shrestha AB, Mehta A, Zahid MJ, Candelario K, Shrestha S, Pokharel P. Ghaffari S. A review of pericardial diseases: clinical, ECG and hemodynamic features and management.Cleve Clin J Med. 2000.;67(12):903-14.doi: 10.3949/ccjm.67.12.903.31.Mirabel M, Luyt CE, Leprince P, et al.Outcomes, long-term quality of life, and psychologic assessment of fulminant myocarditis patients rescued by mechanical circulatory support.Crit Care Med.2011.39:1029-35.doi: 10.1097/CCM.0b013e31820ead45This article is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited and it is not used for commercial purposes; 2023, Manan MR et al., Applied Systems and Discoveries Journals.